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ToxSci Advance Access published online on August 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn165
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Potential relationship between hepatobiliary osteopontin and peroxisome proliferator-activated receptor {alpha} expression following ethanol-associated hepatic injury in vivo and in vitro

Jin-Hyung Lee*, Atrayee Banerjee*, Yoshi Ueno{dagger} and Shashi K. Ramaiah*,{ddagger}

* Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA {dagger} Division of Gastroenterology, Graduate School of Medicine, Tohoku University, Sendai, Japan

{ddagger} Corresponding Author: Shashi K. Ramaiah, DVM, PhD, DACVP, DABT, Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, MS- 4467, College Station, TX 77843-4467, Tel: (979) 458-4725, Fax: (979) 845-9972, E-mail: sramaiah{at}cvm.tamu.edu

Received May 1, 2008; revision received August 5, 2008; accepted August 6, 2008


  Abstract

Osteopontin (OPN) up-regulation is known to mediate hepatic inflammation in a rodent model of alcoholic liver disease (ALD) and alcohol ingestion is reported to inhibit hepatic peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) activity leading to hepatic steatosis and inflammation. Therefore, the objective of this study was to investigate the potential relationship between the anti-inflammatory PPAR{alpha} and proinflammatory OPN in rats and mice livers, and cell cultures of hepatocytes and biliary epithelium. Experiments were designed to evaluate the influence of ethanol (EtOH), lipopolysaccharide (LPS), and acetaldehyde (ACA) on OPN and PPAR{alpha} expression levels in vivo (rats and mice) and in vitro (hepatocytes and biliary epithelium). Adult Sprague-Dawley rats and C57BL6 mice were fed EtOH-containing Lieber-DeCarli liquid diet for 6 weeks and injected with a single dose of LPS. A combination of EtOH and LPS treated rats and mice showed significant induction of hepatic OPN expression compared to the controls. Similarly, cells exposed to physiological doses of EtOH, LPS, a combination of EtOH and LPS, and ACA resulted in increased OPN protein and mRNA expression. Rats and mice in ALD model and cells treated with EtOH and ACA showed down-regulation of PPAR{alpha} mRNA. Also, DNA binding activity of PPAR{alpha} to PPAR response element (PPRE) was significantly reduced following treatment. Over-expression of PPAR{alpha} rescued the reduced PPAR{alpha} activity and PPAR{alpha} agonist, bezafibrate, elevated PPAR{alpha} activity after treatment of EtOH, LPS, and ACA when cells were exposed by bezafibrate. To further delineate the potential relationship between OPN and PPAR{alpha}, OPN-/- mice showed no change of PPAR{alpha} mRNA level although wild-type mice showed down-regulation of PPAR{alpha} mRNA after EtOH treatment. In conclusion, the current study suggests that OPN is induced by ethanol and its metabolite ACA and opposite relationship likely exist between PPAR{alpha} and OPN expression within the liver during ALD.

Key Words: bezafibrate; ethanol; osteopontin; peroxisome proliferator-activated receptor {alpha}.


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